Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells.
Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPARgamma induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H(2)O(2) levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulin-resistant cells, suggesting that GPx3 is required for the regulation of PPARgamma-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPARgamma is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.
Chung
Sung Soo
SS
Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea.
Kim
Min
M
Youn
Byoung-Soo
BS
Lee
Nam Seok
NS
Park
Ji Woo
JW
Lee
In Kyu
IK
Lee
Yun Sok
YS
Kim
Jae Bum
JB
Cho
Young Min
YM
Lee
Hong Kyu
HK
Park
Kyong Soo
KS
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D003920:Diabetes Mellitus / Q000201:enzymology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000187:drug effects / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000201:enzymology*; D047495:PPAR gamma / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology
D000975:Antioxidants; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D006861:Hydrogen Peroxide; C486484:GPX3 protein, human; D005979:Glutathione Peroxidase; D005947:Glucose